Atrial fibrillation (AF) is a common cardiac disorder characterized transient to permanent replacement of the normal, coordinated electrical impulses generated by the sinoatrial (SA) node by disorganized electrical impulses originating in the atria and pulmonary veins. An irregular heartbeat results.
AF is classified into three classes after the first detected AF event, each with a greater proportion of time spent in AF. Paroxysmal atrial fibrillation (PAF) patients have multiple self-terminating episodes of arrhythmia that can span from >30 seconds to days, but they must self-terminate in less than seven days. PAF is typically responsive to chemical or electrical cardioversion, or the reestablishment of sinus rhythm. Persistent AF is characterized by episodes that can last more than 7 days, but are generally still responsive to cardioversion. Permanent AF is characterized by continuous AF that is unresponsive to efforts to reestablish sinus rhythm. The natural tendency of AF is to become a chronic condition, advancing from PAF to persistent and eventually to permanent AF.
The process whereby AF advances from first event to PAF to persistent and finally permanent AF is called atrial remodeling. Remodeling is broadly comprised of electrical remodeling and structural remodeling though thrombotic remodeling is often considered a separate part of the progression and dependent upon electrical remodeling. Electrical remodeling refers to the changes primarily affecting the excitability and electrical activity of the atrial myocytes. Such remodeling is fairly rapid, happening on the hours to days timescale. Structural remodeling refers to the changes in myocyte number, chamber size, interstitial collagen deposition, and fibroblast proliferation, which is a slower process that occurs on the months to years timescale. All types of remodeling have adverse medical consequences such as an increased risk of clot formation and stroke. Remodeling can lead to loss of the primary mechanical function of the atrium, the properly coordinated diastolic filling of the left and right ventricles, which in turn can lead to congestive heart failure.
Thrombotic remodeling refers to increase in thrombogenicity of the atria in AF patients. AF is associated with the upregulation of thrombogenic factors, for example fibrinogen, fibrin D-dimer, and von Willebrand factor, that, when combined with decreased blood flow and left atrial stasis in AF, promotes thrombogenesis (Marin, F, et al., Heart. 2004 October; 90(10):1162-6; Lip G Y, et al., Br Heart J. 1995 June; 73(6):527-33). Patients with first onset AF, PAF, as well as persistent and permanent AF exhibit such upregulation (Marin, F, et al., supra; Lip, G Y, et al., Am Heart J. 1996 April; 131(4):724-30). The presence of such upregulation for first onset AF suggests that thrombogenic remodeling takes place in the hours timescale, similar to electrical remodeling. It is thought that these are important early biomarkers of increased risk of clot formation and stroke. It has only recently been recognized, counter to prior conventional wisdom, that PAF or new onset AF carries a significant stroke risk.
Remodeling, particularly electrical remodeling, appears to be reversible, and the greater the time a patient spends in normal sinus rhythm after some atrial remodeling has occurred, the greater the reversal of remodeling, and the lower the probability of AF recurrence (Hobbs et al., Circulation Hobbs et al. 101(10): 1145. (2000)). Several parameters can be measured to determine the level of remodeling or reversal of remodeling, including atrial fibrillation cycle length (AFCL). AFCL decreases as a patient spends more time in AF and, conversely, AFCL increases with increased time spent in normal sinus rhythm. Longer AFCLs reflect greater atrial refractoriness and, in general, resistance to AF. It is accepted in clinical practice that “AF begets AF”. This may be because increased time in AF is associated with decreased AFCL making it more difficult over time for the AF to either terminate sponateously, or be to cardioverted back to normal sinus rhythm by direct current or drugs. Hobbs et al., (supra) found that AFCL at the right atrial appendage increased an average of 6 milliseconds when a patient was cardioverted from AF and spent time in NSR, which was a statistically significant change in AFCL (and atrial refractoriness) that represented greater resistance to AF. At the distal coronary sinus, a statistically significant increase in AFCL of 6 milliseconds was observed after the first cardioversion and time spent in NSR. Thus, measurement of a patient's AFCL before treatment and over time can reflect the extent of reversal of electrical remodeling. Similarly, other measures of refractoriness, such as the shortest coupling interval of atrial premature beats and directly measured refractory periods after cardioversion, can indicate the extent of electrical remodeling and remodeling reversal.
While there are many factors that influence stroke risk, such as age, heredity, race, sex, prior stroke, hypertension, cardiac failure, diabetes, and others, a significant risk factor for stroke is AF. The characteristic lack of coordinated atrial contraction can result in clot formation in the atrium, and particularly the left atrial appendage (assisted by the localized prothrombotic state due to thrombotic remodeling). The increased stasis of blood in the atrium due to loss of mechanical function (i.e. contraction), combined with poorly understood changes in the thrombogenicity of the atrial endocardial surface in AF is thought to be the primary basis for clot formation in the left atrium and left atrial appendage in AF. There is good precendent for this. For example the combination of stasis and increased thromogenicity of the underlying surface when they occur in the veins of the calf are well accepted to be the eitiology of clot formation in the legs known as deep venous thrombosis (DVT).
If the blood clot leaves the atria and becomes lodged in an artery in the brain, a stroke results. This is known as an embolic or more precisely as a thromboembolic cerebrovascular accident (CVA). If the clot travels to the periphery, other damage can occur, such as bowel ischemia. This event is known as systemic thromboembolic event. Approximately 15% of strokes occur in people with AF, a number that is likely artificially low due to cryptogenic stroke, or stroke whose cause is indeterminate, actually being caused by formerly undiagnosed or unrecognized AF. Approximately one third of strokes are classified as cryptogenic, of which nearly one quarter were associated with undiagnosed AF (Tayal, et al., Neurology. 2008 Nov. 18; 71(21):1696-701). Diagnosed AF is associated with a four- to five-fold increase in stroke risk (Wolf P A, Abbott R D, Kannel W B, Arch Intern Med. 1987 September; 147(9):1561-4; Stroke. 1991 August; 22(8):983-8).
Regarding the relative risk of the subtypes of AF, the benchmark study is known as ACTIVE W (Hohnloser S H, et al., J Am Coll Cardiol. 2007 Nov. 27; 50(22):2156-61). ACTIVE W investigated the incidence of stroke in 1202 paroxysmal AF patients versus a combined group of 5495 patients with either persistent or permanent (i.e., “sustained”) AF. The investigators found that patients with paroxysmal AF have a similar risk of stroke as those with sustained AF, and that despite the statistically significantly lower CHADS2 score in the paroxysmal AF population (CHADS2 of 1.79 versus 2.04, p<0.00001). CHADS2 is a clinical prediction rule for estimating the risk of stroke in AF patients comprising Cardiac failure, Hypertension, Age, Diabetes, and Stroke or transient ischemic event (TIA) [doubled], wherein the higher a patient's score, the greater their risk of stroke. In an observational study, Capucci et al (J Am Coll Cardiol. 2005 Nov. 15; 46(10):1913-20) reported in PAF an increased risk of stroke for patients with episodes longer than 24 hours and suggested that such information be used to guide anticoagulation regimen. The reference fails to offer any teaching or suggestion that a drug could or should intervene and modulate AF episode duration thereby offering therapeutic intervention for stroke as with the instant invention. Again, Capucci's teaching relates to guiding anticoagulation therapy in AF not antiarrhythmic therapy. In fact the conventional accepted medical belief, as a result of multiple antiarrhythmic drug studies over many years that failed to shown any reduction in stroke rate with antiarrhytmic drug therapy, has been that, an antiarrhythmic drug would have no benefit or role in reducing stroke risk in AF.
Atrial fibrillation can be symptomatic or asymptomatic. Symptomatic AF can be characterized by, for example, palpitations, dyspnea, chest discomfort, fatigue, dizziness, syncope, exercise intolerance, and transient ischemic attack (TIA), and is often found upon examination for such symptoms. Asymptomatic AF, due to its lack of symptoms, is generally found by happenstance, such as during a routine examination or preoperative assessment. Page et al. (Circulation. 1994 January; 89(1):224-7), found that asymptomatic AF is more than 12-fold more prevalent than symptomatic AF, which is particularly significant given that asymptomatic AF is thought to confer no less risk than symptomatic AF with regard AF-related complications (Savelieva, I. Camm, I. John, J Intery Card Electrophysiol. 2000 June; 4(2):369-82). From the results of Tayal et al on the etiology of cryptogenic stroke described above (Tayal, et al., Neurology. 2008 Nov. 18; 71(21):1696-701) it is clear that asymptomatic PAF or undiagnosed PAF can prose a major threat of stroke in often otherwise seemingly health people.
Two primary chemotherapeutic paradigms are utilized to treat AF, one to address the AF itself, and the other addresses stroke. Chemotherapeutic treatment of AF includes heart rate control drugs (such as digoxin), beta-blockers, and calcium channel blockers (such as verapamil and diltiazem), which seek to reduce the heart rate to one that is closer to normal to reduce symptoms, and rhythm control drugs (such as amiodarone, dronedarone, budiodarone, vernakalant, celivarone and AZD-1305), which seek to restore and maintain the regular heart rhythm. It has been widely accepted for many years that these treatment strategies offer no protection from stroke in AF, and that the only effective stroke prevention treatment for patients with AF is to administer an effective dose of an (oral) anticoagulant (blood thinner) on a chronic basis as described later.
Regarding the relative effectiveness of rhythm control and rate control drugs on AF, the benchmark study is known as AFFIRM (Wyse D G, et al., N Engl J. Med. 2002 Dec. 5; 347(23):1825-33). AFFIRM compared rhythm control and rate control in 4060 AF patients with an endpoint of overall mortality. The study demonstrated that management of AF with rhythm control offers no survival advantage over rate control, and that rate control potentially offers advantages, such as a lower risk of adverse events. Regarding stroke, the AFFIRM study showed similar numbers (rate control: 77 events among 2027 patients; rhythm control: 80 events among 2033 patients), indicating, like ACTIVE W, that more time spent in AF does not correlate with a greater risk of stroke and that antiarrhythmic drug therapy failes to prevent strokes in AF. Additional studies came to the same conclusion, such as PIAF (Hohnloser S H, et al. Lancet 2000; 356:1789-94), STAF (Carlsson J, et al. J Am Coll Cardiol 2003; 41:1690-6), RACE (Van Gelder I C, et al., N Engl J Med 2002; 347:1834-40), HOT CAFÉ (Opolski G., et al, Chest 2004; 126: 476-86) and AF-CHF (Roy D, et al., N Engl J Med 2008; 358:2667-77).
A standard study design for new anti-arrhythmic drugs involves TTFR, or time to first recurrence of AF. Two examples of such a study are EURIDIS and ADONIS for dronedarone (Singh B N, et al., N Engl J. Med. 2007 Sep. 6; 357(10):987-99). In EURIDIS and ADONIS, 1237 (combined) AF patients were given placebo (409) or dronedarone (828), and followed for a year. Follow-up consisted of two 12-lead electrocardiograms, 10 minutes apart on days 2, 3, and 5, as well as at months 3, 5, 7, and 10 post-randomization, or whenever they had symptomatic AF. The primary end point was the time from randomization to the first documented recurrence of AF, defined as an episode lasting for at least 10 minutes and confirmed by two consecutive recordings taken 10 minutes apart. EURIDIS and ADONIS demonstrated a significant increase in TTFR compared to placebo.
Nevertheless, EURIDIS and ADONIS, as well as other TTFR trials, have weaknesses. Increased TTFR assumes less overall AF, but detection still occurs by chance, i.e., on preplanned days 2, 3, and 5, after months 3, 5, 7, and 10, or when AF is symptomatic (the only non-chance identification of AF). However, asymptomatic AF accounts for at least 12× more AF than symptomatic AF, and stroke risk of both is thought to be the same. Thus, TTFR trials like EURIDIS and ADONIS may quantify an increase in TTFR, but they significantly under represent the amount of time a patient spends in AF. That is, they fail, except by chance, to identify and account for the significant amount of asymptomatic AF, and they fail to characterize AF and how AF might change under influence of study drug or comparator. As a consequence, one of ordinary skill in the art has no guidance regarding the present invention.
A recent outcome study, ATHENA, followed the EURIDIS and ADONIS TTFR studies on dronedarone (Hohnloser S H, et al., N Engl J. Med. 2009 Feb. 12; 360(7):668-78. Erratum in: N Engl J. Med. 2009 Jun. 4; 360(23):2487; Connolly S J, et al., Circulation. 2009 Sep. 29; 120(13):1174-80). In ATHENA, of 4628 total patients, 2327 were given placebo and 2301 were given dronedarone, and the primary study outcome was time to first hospitalization due to cardiovascular events or death from any cause. Contrary to the vast body of clinical studies and literature, treatment with an anti-arrhythmic was correlated with a reduction in stroke. However, confounding that observation was the inexplicable finding in ATHENA that patients with only AF or atrial flutter on all ECGs through out the 2 years of the study (i.e., those who had degraded into permanent AF, which is unresponsive to anti-arrhythmics), experienced 2 strokes versus 8 for the placebo, suggesting a possible undetermined imbalance between the treatment groups. Moreover, the study authors describe how study drug reduced blood pressure and that reductions in blood pressure are correlated with decreased stroke. It is well known that blood pressure reduction reduces stroke risk due to non-embolic cerebrovascular accidents. The failure to properly ajudicate the cause of these strokes in AF in the ATHENA study fails to teach or suggest whether the cause of the reduction in strokes was due to preventing embolic strokes from the left atrium, hypertensive strokes, strokes due to in situ thrombosis in the cerebral arteries, some other cause, or a combination of some or all of the above. The study authors also describe that study drug reduced heart rate and that such an effect could directly reduce stroke risk by preventing hypotension. To the extent that the study authors say that a reduction in overall AF could have influenced stroke risk, they provide no teaching or suggestion regarding how reduced AF may exert this effect (which is contrary to the vast body of knowledge in the art that anti-arrhythmics have no effect on stroke, e.g., AFFIRM), or how their drug may specifically affect AF. They even summarize their study by stating “the results of the present study should not be interpreted to indicate that dronedarone might be a replacement for AC therapy or a treatment for stroke prevention.” (supra). Thus, ATHENA provides no teaching or suggestion regarding how an anti-arrhythmic could affect stroke risk, beyond blood pressure and heart rate, and in particular no teaching or suggestion of the present invention.
The other primary AF treatment paradigm is anticoagulation as a means to reduce stroke risk. Anticoagulation is the only proven and currently accepted drug therapy known to reduce stoke risk in AF. In patients with AF, warfarin prevents 64% of strokes (Hart R G, Pearce L A, Aguilar M I. Ann Intern Med. 2007 Jun. 19; 146(12):857-67). Warfarin, despite being effective, is inconvenient to use and is susceptible to a significant number of drug-drug interactions, which complicate its use. As a consequence, other anticoagulants are being developed that are vitamin-K epoxide reductase inhibitors (for example, tecarfarin), direct thrombin inhibitors (for example, AZD-0837; dabigatran etexilate, dabigatran, ximelagatran; melagatran, and argatroban), or Factor Xa inhibitors (for example, apixaban, rivaroxaban, YM466, betrixaban, and edoxaban).
In a phase 2 clinical trial, tecarfarin (ATI-5923) demonstrated an statistically significant increase in time in therapeutic range (TTR), defined as an International Normalized Ratio (INR) of between 2.0 and 3.0, as compared to warfarin (p=0.0009). TTR was 71.5% versus 59.3% for the same exact patient population when they were previously on warfarin. The proportion of time spent in more thrombogenic INR ranges were also reduced compared to warfarin. On warfarin, patients had INR ratios between 1.5 and 1.9 22.4% of the time versus 14.2% for tecarfarin. On warfarin, patients had INR ratios below 1.5 3.9% of the time versus 1.2% for tecarfarin. Similar results were seen for higher INR ratios, which are representative of higher risk of hemorrhage. Greater time in therapeutic range correlates with increased life expectancy, from approximately 50% life expectancy at 5 years for 32% TTR, to about 65% at 59% TTR, to about 75% at 72% TTR and about 85% at 84% TTR (Currie et al., Heart 2006(92)196-200). Regarding outcomes, a 10% decrease in TTR results in a 29% increase in mortality, a 10% increase in ischemic stroke risk and a 12% increase in all thromboembolic events (Jones et al., Heart 2005(91)472-477). Thus, tecarfarin should be an important AC for use in AF patients to reduce stroke.
The results of an outcome trial for a direct thrombin inhibitor (DTI), dabigatran etexilate, were recently published (Connolly S J, et al., N Engl J. Med. 2009 Sep. 17; 361(12):1139-51; Gage BF, N Engl J. Med. 2009 Sep. 17; 361(12):1139-51). The RE-LY trial followed over 18000 patients for an average of two years, with a primary outcome of systemic embolism or stroke. Dabigatran at 150 mg proved superior to warfarin with respect to stroke and noninferior with respect to major bleeding; whereas, dabigatran at 110 mg proved noninferior to warfarin with respect to stroke and superior with respect to major bleeding. Amiodarone was being used concomitantly in approximately 2000 of the 18000 enrolled patients, and those patients appeared to show a trend toward lower stroke risk in contrast to other trials, but the trend was not statistically significant. Moreover, dabigatran is a P-glycoprotein (P-gp) substrate, and amiodarone is a P-gp inhibitor, so the trend was attributed to a pharmacokinetic interaction between amiodarone and dabigatran through P-gp resulting in an increased serum concentration of dabigatran and hence greater efficacy in reducing stroke risk in AF. Further bolstering this explanation is the fact that quinidine, another anti-arrhythmic that was originally permitted in the study, was later removed because the combination of dabigatran and quinidine was unfavorable to patient health. Quinidine is a particularly potent P-gp inhibitor and because it is a more potent inhibitor of P-gp than amiodarone, it raised dabigatran blood levels to unacceptably high levels. Quinidine is now specifically contraindicated in dabigatran product literature.
Clarfication of the recommended and accepted current treatments for preventing stroke in AF can be found in practice guidelines. There are three professional bodies in the US that issue guidelines to physicians on how to reduce stroke risk in AF; the ACC (American College of Cardiology), the AHA (American Heart Association), and the ACCP (American College of Chest Physicians). All three concur that an anticoagulant can, and should be used to prevent stroke in AF especially in patients who have a CHADS2 score of 1 or greater. As of the date of application none of the current guidelines from these three professional bodies recommend, or even suggest that, an antiarrhythmic drug can be used to reduce stroke risk in AF.
Given the above, the prior art fails to teach or suggest that budiodarone can serve as a therapeutic intervention for stroke by reducing AF episode duration. Likewise, there is no teaching or suggestion than AF episode duration can be lowered as substantially as described herein, or that budiodarone can prevent or reverse atrial remodeling through reduction in AF episode duration.
Given the above, the prior art fails to teach or suggest that the administration of an anti-arrhythmic and an anticoagulant can serve as a synergistic therapeutic intervention for stroke by reducing AF episode duration and inhibiting thrombogenesis. Likewise, there is no teaching or suggestion than AF episode duration can be lowered as substantially as described herein, or that the administration of an anti-arrhythmic and an anticoagulant can prevent or reverse atrial remodeling through reduction in AF episode duration.
Given the above, the prior art fails to teach or suggest that the administration of budiodarone and an anticoagulant can serve as a synergistic therapeutic intervention for stroke by reducing AF episode duration and inhibiting thrombogenesis. Likewise, there is no teaching or suggestion than AF episode duration can be lowered as substantially as described herein, or that the administration of budiodarone and an anticoagulant can prevent or reverse atrial remodeling through reduction in AF episode duration.